The predisposition to stress-related mood disorders likely involves a genetic vulnerability to increased stress sensitivity and may be a direct result of a dysregulation in central corticotrophin releasing factor (CRF) pathways. The focus of this grant proposal is the examination of central CRF pathway dysregulation involvement with increased susceptibility for stress-related mood disorders via interactions with serotonin (5-HT) neurocircuitry. Our studies utilize a genetic mouse model in which CRF expression is elevated in the amygdala in addition to showing increased stress responsivity under conditions of homeostatic challenge. In order to influence synaptic 5-HT levels in our behavioral, biochemical, and molecular comparisons, we will treat animals with the SSRI fluoxetine. The following aims are proposed using an integrated view of how stress pathways impact emotional behavior, specifically the interactions of CRF and 5-HT neurocircuitry. Aim 1 will examine the possible role of CRF dysregulation in the development of stress-related mood disorders resulting from an impact on serotonin pathways by examining behavioral stress responses. Aim 2 will then examine the molecular and biochemical changes corresponding with behavioral outputs following fluoxetine treatment. We will study alterations in CRF and 5-HT receptor gene expression, protein levels and biochemical state, and receptor occupancy in specific brain regions. In Aim 3 we will create a conditional, inducible, site-specific mouse deficient for CRFR1 in 5-HT producing cells in order to more directly examine the specific interaction of elevated central CRF expression and 5-HT pathways impacting stress-sensitive behaviors. These mice will be crossed with our CRFR2-deficient mice to produce mice with elevated amygdalar CRF and deficient in CRFR1 in 5-HT cells. We hypothesize that results from these proposed studies will demonstrate an involvement of a dysregulation of CRF pathways in alterations in 5-HT neurotransmission leading to a predisposition to stress-related mood disorders.